TIME: Tractography-Informed myelin estimation

Abstract

Investigating myelin integrity within multiple sclerosis (MS) lesions and in normal-appearing white matter is crucial for understanding demyelination and remyelination processes. While most approaches assess global myelin changes or compare lesions with homologous regions in healthy controls, they do not allow direct within-tract comparisons between lesional and non-lesional tissue. We introduce the tractography-informed myelin estimate (TIME), a novel map designed to quantify tract-specific myelin loss. TIME integrates tractography with myelin-sensitive imaging, such as myelin volume fraction, to compare lesional and non-lesional segments within the same white matter tract. By modeling local deviations from the expected myelin volume fraction signal along streamlines, TIME captures tract-specific myelin damage while accounting for within-tract variability. TIME is based on a microstructure-informed tractography framework, with an extra compartment to model signal loss caused by lesions. We evaluated TIME in 159 MS patients, assessing its association with neurological disability at baseline and longitudinally over a median follow-up of two years. At baseline, higher myelin loss captured by TIME was significantly associated with worse disability (β = 0.14, p = 0.015). Longitudinally, greater baseline disability predicted faster TIME-quantified myelin loss, which was in turn associated with a higher risk of disability worsening. In contrast, lesion-averaged myelin volume fraction showed no significant associations with either baseline disability or its progression. TIME provides a detailed, tract-specific assessment of myelin damage, providing greater sensitivity than conventional metrics, highlighting its potential as a biomarker in MS.

Keywords: Focal Lesions; Multiple Sclerosis; Myelin; Tractography.

Fig. 1

Graphic illustration of the Tractography-Informed Myelin Estimate (TIME) computation. A streamline passing through a lesion is internally divided into voxel-wise fragments. The myelin content along a streamline is assumed to be constant across all voxels it traverses (in this example, equal to ten). In voxels where the signal deviates from this expected value (e.g., the light-blue voxel showing a value of six instead of ten), the difference is attributed to the lesion compartment. This discrepancy is reflected in the TIME map, where the same light-blue voxel is assigned a value of four, representing the estimated myelin loss in that voxel relative to its neighbors along the streamline. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The image shows a graphic illustration of the pipeline. The patients underwent the MRI scanner twice, two years apart. For each time point, we generated a whole-brain tractogram and segmented the white matter lesions, which were subsequently manually corrected. The lesion mask, the tractograms, and the myelin-sensitive map were used as input to the MySD framework sensitive to lesions, which returned two maps to us. One map shows the bundle-specific myelin content estimated by the model, and a second map provides the values of tractography-informed myelin estimate (TIME), in which the myelin lost by a bundle of neurons in the area affected by the lesion is estimated. Afterward, TIME values in the lesions and the myelin content in MVF maps are compared and investigated for their correlations with the EDSS clinical scale in the whole WM. In addition, the correlation between the TIME values and the patient’s clinical worsening over the years is estimated, and the prediction of myelin damage is compared to the baseline EDSS value. TP: Time Point, MySD: Myelin Streamline Decomposition, MVF: Myelin Volume Fraction, TIME: Tractography-Informed Myelin Estimate, WML: White Matter Lesion.

Fig. 3

Correlation between the EDSS adjusted for disease duration, age, and sex, and the values in the WMLs computed by averaging the MVF values on the left and by Tractography-informed myelin loss values on the right. EDSS: Expanded Disability Status Scale, MVF: Myelin Volume Fraction, TIME: Tractography-Informed Myelin Estimate, WML: White Matter Lesion.

Fig. 4

Correlation between the EDSS estimated at baseline adjusted for disease duration, age, and sex, and the remyelinated lesion ratio in 1) average MVF values within WMLs (left) and 2) tractography-based myelin damage in WMLs (right). EDSS_BL: Expanded Disability Status Scale at Baseline, MVF: Myelin Volume Fraction, TIME: Tractography-Informed Myelin Estimate, WML: White Matter Lesion.

Fig. 5

Correlation between the EDSS estimated at baseline and the annual percentage change in 1) average MVF values within WMLs (left) and 2) tractography-based myelin damage in WMLs (right). EDSS_BL: Expanded Disability Status Scale at Baseline, MVF: Myelin Volume Fraction, TIME: Tractography-Informed Myelin Estimate, WML: White Matter Lesion.

Fig. 6

In the plot, the MVF average and tractography-informed myelin loss annual percentage changes in WMLs are reported in the two groups of MS patients: worsening and not worsening. MVF: Myelin Volume Fraction, TIME: Tractography-Informed Myelin Estimate, WML: White Matter Lesion.